We have studied the mechanisms of activation, proliferation, and differentiation of human lymphocytes, particularly B cells, at the cellular and molecular levels. We have identified and purified a high molecular weight B cell growth factor (HMW-BCGF) and its cellular receptor (BA5) which is a 90 Kd heterodimer with at least 1 associated protein and which is assembled from smaller precursor proteins. We have demonstrated that HMW-BCGF acts selectively on certain subsets of B cells. B cell proliferation can also be modulated by the Ba and Bb fragments of the complement component factor B, and Clq was also shown to induce IgM secretion by normal B cells. We have purified a 30 Kd B cell differentiation factor (BCDF) from a T4+ clone. We are at various stages of cloning the genes for our HMW-BCGF, its receptor, and the BCDF. We demonstrated that LTC4 and PGE2 inhibited Ig secretion establishing a link in our system between the inflammatory and immune responses. We have demonstrated that transforming growth factor (TGF)-beta is a potent inhibitor of B cell activation. We have extended our studies delineating the BCGF activity of tumor necrosis factor (TNF)-alpha by binding and cross-linking studies of factor to receptor and have demonstrated that there is a marked upregulation of TNF-alpha receptors following B cell activation. Lymphotoxin (LT), a structurally and functionally related protein to TNF, was also found to have BCGF activity, and Northern blots demonstrated the rapid induction of messenger RNA for LT in mitogen- activated T cells. Using chemical crosslinking with 125I-IL-2, we have identified a second IL-2 binding protein (p70) which is distinct from the Tac protein. The presence of the p70 protein on resting T cells, natural killer (NK) cells, and SKW 6.4 B cell lines suggests that IL-2 binding to this receptor accounts for the previous observations that these Tac negative cells can respond to IL-2. Finally we have demonstrated 2 proteins (p50 and p90) which likely constitute the IFN-gamma receptor on B cells.